Preparation and Characterization of Gelonin-Melittin Fusion Biotoxin for Synergistically Enhanced Anti-Tumor Activity
文献类型：期刊论文
| 作者 | Shin, Meong Cheol1,7,8; Min, Kyoung Ah1,6,7,8; Cheong, Heesun5; Moon, Cheol4; Huang, Yongzhuo3 ; He, Huining2; Yang, Victor C.2,7
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| 刊名 | PHARMACEUTICAL RESEARCH
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| 出版日期 | 2016-09 |
| 卷号 | 33期号:9页码:2218-2228 |
| 关键词 | cancer gelonin melittin ribosome inactivating protein toxin |
| ISSN号 | 0724-8741 |
| DOI | 10.1007/s11095-016-1959-4 |
| 文献子类 | Article |
| 英文摘要 | To investigate the applicability of fusion biotoxins combining pore-forming toxins (PFTs) and ribosome-inactivating proteins (RIPs) for the anti-cancer treatment. Membrane active PFTs tend to destabilize cell membranes of tumor cells, but lack a warhead inducing significant cause of cell death. Cell-impermeable RIPs possess a powerful warhead, yet not able to enter the tumor cells. To address these challenges for anti-tumor effects, we introduced a fusion strategy of conjugating melittin (a PFT) and gelonin (a type 1 RIP) via chemical and recombinant methods, followed by in vitro assays and in vivo animal studies. In vitro characterization results confirmed that the chimeric gelonin-melittin fusion proteins retained equivalent intrinsic activity to that of unmodified gelonin in inhibiting protein translation. However, chemically conjugated gelonin-melittin (cGel-Mel) and recombinant chimeric gelonin-melittin fusion (rGel-Mel) exhibited greater cell uptake, yielding a significantly enhanced cytotoxic activity over treatment of gelonin, melittin or physical mixture of gelonin and melittin. Remarkably, cGel-Mel and rGel-Mel displayed 32- and 10-fold lower IC50 than gelonin in the cell lines. The superior anti-tumor efficacy of multivalent cGel-Mel to monovalent rGel-Mel suggested that valency could be a crucial factor for the extent of melittin-mediated cell uptake. Tumoricidal effects observed from animal studies were in good accordance with our findings from the cellular assays. This study successfully demonstrated that fusion of biotoxins could provide a simple yet effective way to synergistically augment their anti-tumor activity. |
| WOS关键词 | RIBOSOME-INACTIVATING PROTEINS ; IMMUNOTOXINS ; CANCER ; TOXIN ; PEPTIDES ; CELLS ; CYTOTOXICITY ; CONJUGATION ; MECHANISM ; MEMBRANES |
| 资助项目 | NSFC A3 Foresight Program[81361140344] ; National Key Basic Research Program of China[2013CB932502] ; National Natural Science Foundation of China (NSFC)[81402856] ; National Institutes of Health R01 Grants[CA114612] ; Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology[NRF-2015R1A6A3A01020598] ; Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology[NRF-2015R1C1A1A02036781] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000381260000013 |
| 出版者 | SPRINGER/PLENUM PUBLISHERS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275919]  |
| 专题 | 药物制剂研究中心 |
| 通讯作者 | Yang, Victor C. |
| 作者单位 | 1.Gyeongsang Natl Univ, Coll Pharm, 501 Jinju Daero, Jinju 52828, Gyeongnam, South Korea; 2.Tianjin Med Univ, Tianjin Key Lab Technol Enabling Dev Clin Therape, Sch Pharm, Tianjin 300070, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, 501 Hai Ke Rd, Shanghai 201203, Peoples R China; 4.Sunchon Natl Univ, Coll Pharm, 255 Jungang Ro, Sunchon 57922, Jeonnam, South Korea; 5.Natl Canc Ctr, Div Canc Biol, Comparat Biomed Res Branch, 323 Ilsan Ro, Goyang 10408, Gyeonggi Do, South Korea; 6.Inje Univ, Coll Pharm, 197 Injero, Gimhae 50834, Gyeongnam, South Korea; 7.Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA; 8.Gyeongsang Natl Univ, Pharmaceut Sci Res Inst, 501 Jinju Daero, Jinju 52828, Gyeongnam, South Korea; |
| 推荐引用方式 GB/T 7714 | Shin, Meong Cheol,Min, Kyoung Ah,Cheong, Heesun,et al. Preparation and Characterization of Gelonin-Melittin Fusion Biotoxin for Synergistically Enhanced Anti-Tumor Activity[J]. PHARMACEUTICAL RESEARCH,2016,33(9):2218-2228. |
| APA | Shin, Meong Cheol.,Min, Kyoung Ah.,Cheong, Heesun.,Moon, Cheol.,Huang, Yongzhuo.,...&Yang, Victor C..(2016).Preparation and Characterization of Gelonin-Melittin Fusion Biotoxin for Synergistically Enhanced Anti-Tumor Activity.PHARMACEUTICAL RESEARCH,33(9),2218-2228. |
| MLA | Shin, Meong Cheol,et al."Preparation and Characterization of Gelonin-Melittin Fusion Biotoxin for Synergistically Enhanced Anti-Tumor Activity".PHARMACEUTICAL RESEARCH 33.9(2016):2218-2228. |
入库方式： OAI收割
来源：上海药物研究所
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